溶酶体酶PPT1介导的细胞稳态调控及疾病发生的研究进展

棕榈酰蛋白质硫酯酶1(palmitoyl protein thioesterase 1,PPT1)是一种溶酶体酶,具有对蛋白质行使去棕榈酰化修饰的功能,在调控细胞器(如溶酶体、线粒体)功能、脂质代谢和Ca2+转运等方面具有重要作用。PPT1在神经系统疾病和癌症的发生发展中发挥了重要的作用,然而其调控作用机制仍未被完全阐明。本文综述了目前PPT1在脂质代谢调控、物质转运调控、钙稳态调控过程中的作用及最新研究进展,总结并探讨了PPT1在神经系统疾病及肿瘤发生发展中作用及调控机制,为将来更深层次研究PPT1的功能及调控机制并开发相关疾病治疗的新药物提供借鉴和参考。

Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging

Hyperglycemia induces chronic low-grade inflammation(inflammaging),which is a newly identified contributor to diabetes-related tissue lesions,including the inflammatory bone loss in periodontitis.It is also a secondary senescent pattern mediated by an increased burden of senescent cells and senescence-associated secretory phenotype(SASP).Macrophage is a key SASPspreading cell and may contribute to the maintenance of SASP response in the periodontal microenvironment.Using a transgenic diabetic model(BLKS/J-Lepr^(db)/lepr^(db)mice)we identified striking senescence of the periodontium in young(18-wk)-diabetic mice accompanied by amassed p16^(+)-macrophages and enhanced early SASP response.Exposed to high glucose in vitro,bone marrow-derived macrophage(BMDM)revealed a strong GLUT1 m RNA response driving the elevated-glucose uptake.GLUT1 is a representative and facilitative glucose transporter in macrophages with potential roles in hyperglycemia-induced inflammation.In this study,both GLUT1 and the downstream GTPase Rheb expression upregulated in the gingiva of diabetic mice with impaired condition.Furthermore,SASP release and p16/p21 signaling were proven to be triggered by m TOR phosphorylation in BMDM and antagonized by restricting glucose uptake in GLUT1^(-/-)BMDM.Taken together,our findings suggest that elevated-GLUT1 sensor responded to high glucose is important for macrophage senescence and SASP response,generated as a result of hyperglycemia,and it is a potential molecular mechanism for the exacerbation of periodontitis in diabetes.

METTL3-mediated m^(6)A RNA methylation regulates dorsal lingual epithelium homeostasis

The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is the most abundant mRNA modification in eukaryotic cells.How METTL3-mediated m^(6)A modification regulates K14^(+)basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear.Here we show knockout of Mettl3 in K14^(+)cells reduced the taste buds and enhanced keratinocytes.Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds.Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization,but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery.Mechanically,we revealed that the most frequent m^(6)A modifications were enriched in Hippo and Wnt signaling,and specific peaks were observed near the stop codons of Lats1 and FZD7.Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.

重症监护室护士关于患者早期活动知识和态度的调查研究

目的了解ICU护士关于ICU患者早期活动的知识、态度和感知情况。方法采用横断面研究方法。2020年1一8月,应用ICU护士对患者早期活动知识、态度和感知的调查问卷对11所医院的ICU护士进行问卷调查。结果512名符合入选标准的ICU护士完成了问卷调查。其中,护士关于ICU患者早期活动知识的得分为(6.89±2.91)分,知识水平为良好、中等的护士分别占2.5%(13/512)、52.3%(268/512)。31.4%(161/512)的被调查者对ICU患者早期活动持积极态度。在对ICU患者早期活动实施重要性的感知方面,43.0%(220/512)的护士不认为该项措施应该作为重症照护中最优先考虑的措施。不同类别ICU的护士对实施患者早期活动态度的差异有统计学意义(F=3.58,P<0.05);接受过ICU早期活动相关培训的护士知识(7.34±2.78比6.49±2.97,t=3.37,P<0.001)和态度(3.82±0.58比3.52±0.56,t=5.63,P<0.001)得分高于未接受过培训的护士。结论ICU患者早期活动的重要性已被越来越多的重症医护人员认可。但作为主要实施者的护士群体对ICU早期活动的知识、态度和感知仍存在差距。在未来的研究中,有必要进一步明确导致护士在这些方面存在差距的原因并围绕这些差距有针对性地实施干预,同时鼓励更多的护士参与决策,以保障高效、有质量地实施ICU患者早期活动。

Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer

Objective:Mutant KRAS,the principal isoform of RAS,plays a pivotal role in the oncogenesis of colorectal cancer by constitutively activating the RAF/MEK/ERK and PI3K/AKT pathways.Effective targeted therapies are urgently needed.We investigated whether rigosertib,a benzyl styryl sulfone RAS signaling disruptor,could selectively kill KRAS-mutant colorectal cancer cells.Methods:CCK-8 was used to determine the cell viability.Patient-derived tumor and cancer cell xenograft models were used to detect the inhibitory efficacy of rigosertib.Flow cytometry was used to evaluate the apoptosis and cell cycle progression.Apoptosis and cell cycle arrest markers were detected by Western blot.DCFH-DA was used to determine the reactive oxygen species.Immunohistochemistry staining and Western blot were performed to characterize RAS signaling markers in colorectal cancer tissues and cells.Results:Rigosertib(RGS)exhibited a cytotoxic effect against colorectal cancer cells,which was greater in KRAS-mutant cells.Furthermore,RGS induced mitotic arrest and oxidative stress-dependent apoptosis in KRAS-mutant DLD1 and HCT116 cells.Besides,RGS disrupted RAS signaling,and the inhibition of RAS/MEK/ERK was independent of cellular oxidative stress.Using patient-derived xenograft models,the response and tumor inhibition of RGS were significantly higher in the KRAS-mutant subgroup,while p-MEK,p-ERK,and p-AKT levels of RGS-treated tumors were significantly decreased.Finally,in a KRAS-mutant,chemotherapy-resistant patient-derived xenograft model,RGS showed a stronger therapeutic effect than the combination standard therapy involving fluoropyrimidine+oxaliplatin/irinotecan+bevacizumab.Conclusions:These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.

A Deep Neural Collaborative Filtering Based Service Recommendation Method with Multi-Source Data for Smart Cloud-Edge Collaboration Applications

Service recommendation provides an effective solution to extract valuable information from the huge and ever-increasing volume of big data generated by the large cardinality of user devices.However,the distributed and rich multi-source big data resources raise challenges to the centralized cloud-based data storage and value mining approaches in terms of economic cost and effective service recommendation methods.In view of these challenges,we propose a deep neural collaborative filtering based service recommendation method with multi-source data(i.e.,NCF-MS)in this paper,which adopts the cloud-edge collaboration computing paradigm to build recommendation model.More specifically,the Stacked Denoising Auto Encoder(SDAE)module is adopted to extract user/service features from auxiliary user profiles and service attributes.The Multiple Layer Perceptron(MLP)module is adopted to integrate the auxiliary user/service features to train the recommendation model.Finally,we evaluate the effectiveness of the NCF-MS method on three public datasets.The experimental results show that our proposed method achieves better performance than existing methods.

Immediate and long-term outcomes after treat-all among people living with HIV in China:an interrupted time series analysis

Background In 2003,China implemented free antiretroviral therapy(ART)for people living with HIV(PLHIV),establishing an eligibility threshold of CD4<200 cells/μl.Subsequently,the entry criteria were revised in 2012(eligibility threshold:CD4≤350 cells/μl),2014(CD4≤500 cells/μl),and 2016(treat-all).However,the impact of treat-all policy on HIV care and treatment indicators in China is unknown.We aimed to elucidate the immediate and long-term impact of the implementation of treat-all policy in China.Methods Anonymized programmatic data on ART initiation and collection in PLHIV who newly started ART were retrieved between 1 January 2015 and 31 December 2019,from two provincial and municipal Centers for Disease Control and Prevention and ten major infectious disease hospitals specialized in HIV care in China.We used Poisson and quasi-Poisson segmented regression models to estimate the immediate and long-term impact of treat-all on three key indicators:monthly proportion of 30-day ART initiation,mean CD4 counts(cells/μl)at ART initiation,and mean estimated time from infection to diagnosis(year).We built separate models according to gender,age,route of transmission and region.Results Monthly data on ART initiation and collection were available for 75,516 individuals[gender:83.8%males;age:median 39 years,interquartile range(IQR):28-53;region:18.5%Northern China,10.9%Northeastern China,17.5%Southern China,49.2%Southwestern China].In the first month of treat-all,compared with the contemporaneous counterfactual,there was a significant increase in proportion of 30-day ART initiation[+12.6%,incidence rate ratio(IRR)=1.126,95%CI:1.033-1.229;P=0.007]and mean estimated time from infection to diagnosis(+7.0%,IRR=1.070,95%CI:1.021-1.120;P=0.004),while there was no significant change in mean CD4 at ART initiation(IRR=0.990,95%CI:0.956-1.026;P=0.585).By December 2019,the three outcomes were not significantly different from expected levels.In the stratified analysis,compared with the contemporaneous counterfactual,mean CD4 at ART initiation showed significant increases in Northern China(+3.3%,IRR=1.033,95%CI:1.001-1.065;P=0.041)and Northeastern China(+8.0%,IRR=1.080,95%CI:1.003-1.164;P=0.042)in the first month of treat-all;mean estimated time from infection to diagnosis showed significant increases in male(+5.6%,IRR=1.056,95%CI:1.010-1.104;P=0.016),female(+14.8%,IRR=1.148,95%CI:1.062-1.240;P<0.001),aged 26-35(+5.3%,IRR=1.053,95%CI:1.001-1.109;P=0.048)and>50(+7.8%,IRR=1.078,95%CI:1.000-1.161;P=0.046),heterosexual transmission(+12.4%,IRR=1.124,95%CI:1.042-1.213;P=0.002)and Southwestern China(+12.9%,IRR=1.129,95%CI:1.055-1.208;P<0.001)in the first month of treat-all.Conclusions The implementation of treat-all policy in China was associated with a positive effect on HIV care and treatment outcomes.To advance the work of rapid ART,efforts should be made to streamline the testing and ART initiation process,provide comprehensive support services,and address the issue of uneven distribution of medical resources.

Targeting RAS mutants in malignancies:successes,failures,and reasons for hope

RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies.The mutation,isoform(KRAS,HRAS,and NRAS),position,and type of substitution vary depending on the tissue types.Despite decades of developing RAS-targeted therapies,only small subsets of these inhibitors are clinically effective,such as the allelespecific inhibitors against KRASG12C.Targeting the remaining RAS mutants would require further experimental elucidation ofRAS signal transduction,RASaltered metabolism,and the associated immune microenvironment.This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants,including KRAS allele-specific inhibitors,combination therapies,immunotherapies,and metabolism-associated therapies.

Sexual Risk Behavior and Satisfaction Among Men Who Have Sex With Men Living With Detectable HIV Viral Loads:A Nationwide Online Survey in China

Little is known about sexual behavior and satisfaction among men who have sex with men(MSM)with detectable HIV viral loads(VL)in China.This study aims to investigate sexual risk behavior and sexual satisfaction among MSM living with HIV in China,as well as poten-tial predictors.This cross-sectional study was conducted in February 2021 using an anonymous online survey based on WeChat.Data were collected on sociodemographics,sexual behavior,HIV clinical information,sexual satisfaction and mental health.Descriptive sta-tistics,logistic regression and multivariable logistic regression were performed.MSM with detectable HIV VL(VL+)or VL not sure were more likely to report inconsistent condom use,even with HIV-negative/unknown-status regular male partners.Having an HIV-positive regular partner and recreational drug use were positively associated with inconsistent condom use during anal sex among MSM with undetectable VL(VL-).Alcohol use before or during sexual activities was positively associated with inconsistent condom use during anal sex among VL+or VL not sure MSM.A total of 58.3%of participants reported being sexually satisfied.MSM living with HIV who were currently employed,had experienced anal sex in the prior 6 months,had VL-HIV status,or had more frequent ejaculation during sex/masturbation were more likely to report sexual satisfaction.The development of targeted education and interventions to minimize sexual risk behavior among MSM living with HIV is in dire need.Treating sexual dysfunction and developing a reasonable antiretroviral therapy regimen to achieve viral suppression can help promote sexual satisfaction in MSM living with HIV.

METTL5 regulates cranial suture fusion via Wnt signaling

METTL5 is a methyltransferase that mediates eukaryotic 18S ribosomal RNA m^(6)A modification,and its mutations lead to intellectual disability,microcephaly,and facial dysmorphism in patients.However,the role of METTL5 in craniofacial development remains poorly understood.This study demonstrates that Mettl5 knockout mice exhibit poor ossification,widened cranial sutures,and a cleidocranial dysplasia-like phenotype.Deletion of Mettl5 leads to increased proliferation and decreased osteogenic differentiation of suture mesenchymal stem cells.Mechanistically,we find that Wnt signaling is significantly downregulated after Mettl5 knockout.Overall,we reveal an essential role of METTL5 in craniofacial development and osteogenic differentiation of suture mesenchymal stem cells,making METTL5 a potential diagnostic and therapeutic target for craniofacial developmental diseases.

Investigation on the short-term outcome and prognostic impact of predisposition,and precipitants in inpatients with chronic liver disease from Chinese AcuTe on CHronic LIver FailurE(CATCH-LIFE)cohorts

Aim:The study aimed to investigate the short-term outcomes of hospitalized patients with chronic liver disease(CLDs)and assess the prognostic impact of predisposition and precipitants,which currently remains unclear.Methods:The study included 3970 hospitalized patients with CLDs from two prospective longitudinal multicenter studies(NCT02457637 and NCT03641872)conducted in highly endemic hepatitis B virus(HBV)areas.Competing risk analysis was used to evaluate the effect of predispositions,including the etiology and severity of CLDs and precipitants;on sequential 28,90,and 365-day liver transplantation(LT)-free mortality.Results:Among all enrolled patients,76.8%of adverse outcomes(including death and LT)within one year occurred within 90 days.Compared with alcoholic etiology,the association of HBV etiology with poorer outcomes was remarkably on the 28th day(hazard ratio[HR],1.81;95%confidence interval[CI],1.07-3.06;p=0.026);however,and dimin-ished or became insignificant at 90 days and 365 days.Cirrhosis increased the adjusted risk for 365-day(HR,1.50;CI,1.13-1.99;p=0.004)LT-free mortality when compared with noncirrhosis.In patients with cirrhosis,prior decompensation(PD)independently increased the adjusted risk of 365-day LT-free mortality by 1.25-fold(p=0.021);however,it did not increase the risk for 90-day mortality.Neither the category nor the number of precipitants influenced the adjusted risk of 28 or 90-day LT-free mortality.Conclusions:The 90-day outcome should be considered a significant endpoint for evaluating the short-term prognosis of hospitalized patients with CLD.Predisposing factors,other than etiology,mainly affected the delayed(365-day)outcome.Timely effective therapy for CLD etiology,especially antiviral treatments for HBV,and post-discharge long-term surveillance monitoring in cirrhotic patients undergoing PD are suggested to enhance disease management and reduce mortality.

Facile synthesis of two-dimensional MoS_(2)/WS_(2) lateral heterostructures with controllable core/shell size ratio by a one-step chemical vapor deposition method

Heterostructures based on two-dimensional(2D) transition-metal dichalcogenides(TMDCs) possess unique electronic and optical properties, which open up unprecedented opportunities in nanoscale optoelectronic devices. Synthesizing high-quality 2D TMDC heterostructures with different core/shell size ratios is of great significance for practical applications. Here, we report a simple one-step chemical vapor deposition(CVD) method for fabricating MoS2/WS2 lateral heterostructures with controllable core/shell size ratio. An ultrathin MoO3/WO3 film prepared by thermal evaporation was used as the precursor, and a step-like heating process was adopted to separately grow MoS2 and WS2 monolayers by taking advantage of the different melting points of MoO3 and WO3 sources. High-quality MoS2/WS2 lateral heterostructures with sharp interfaces were fabricated by optimizing the key growth parameters. Furthermore, the core/shell size ratio of heterostructures could be easily controlled by changing the thickness ratio of MoO3/WO3 film, and an approximately linear dependence between them is revealed. Compared with MoS2 or WS2 monolayers, the MoS2/WS2 heterostructure exhibited a shortened exciton lifetime owing to the type-Ⅱ energy band alignment, which is conducive to the application of high-performance devices. This work provides a facile strategy for the synthesis of 2D lateral heterostructures with controllable size ratio.

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk.In humans,a large proportion of mental disorders are accompanied by impairments in risk avoidance.One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1(DISC1),and animal models in which this gene has some level of dysfunction show emotion-related impairments.However,it is not known whether DISC1 mouse models have an impairment in avoiding potential risks.In the present study,we used DISC1-N terminal truncation(DISC1-N^(TM))mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze(EPM)and showed reduced social preference in a three-chamber social interaction test.Following EPM tests,c-Fos expression levels indicated that the nucleus accumbens(NAc)was associated with risk-avoidance behavior in DISC1-N^(TM)mice.In addition,in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons(FS)in the NAc were significantly lower in DISC1-N^(TM)mice than in wild-type(WT)mice.In addition,in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin(PV)neurons in the NAc of DISC1-N^(TM)mice than in WT controls.The impairment of risk avoidance in DISC1-N^(TM)mice was rescued using optogenetic tools that activated NAcPV neurons.Finally,inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^(TM)mice during tests on the elevated zero maze.Taken together,our findings confirm an impairment in risk avoidance in DISC1-N^(TM)mice and suggest that reduced excitability of NAc^(PV) neurons is responsible.

Increasing Trend of Summertime Synoptic Wave Train Activity over the Western North Pacific since 1950

The change of summertime synoptic-scale wave train(SWT) activity over the western North Pacific(WNP) since1950 was investigated based on the NCEP–NCAR reanalysis data. It is found that the intensity of SWT has a rising trend, while its structure and phase propagation characteristics remain unchanged. Environmental factors responsible for the rising trend are investigated. By separating the whole period into three warming phases(P1: 1950–1958, P2:1978–1986, and P3: 2006–2014), we found that even though the vertical velocity shows a rising trend, the background low-level vorticity over the monsoon trough region increases from P1 to P2 but decreases from P2 to P3, and so is the low-level barotropic energy conversion(CK). Thus, just the environmental dynamic factor could not explain the continuous rising SWT trend. On the other hand, thermodynamic factor, such as the sea surface temperature(SST), moisture, and atmospheric instability, shows a clear step-by-step increasing trend. A non-dimensional synoptic activity index(SAI) that combines the dynamic and thermodynamic factors is then proposed. This index well captures the observed long-term trend of the SWT intensity.

Ultrasmall Coordination Polymers for Alleviating ROS-Mediated Inflammatory and Realizing Neuroprotection against Parkinson's Disease

Parkinson's disease(PD)is the second most common neurodegenerative disease globally,and there is currently no effective treatment for this condition.Excessive accumulation of reactive oxygen species(ROs)and neuroinflammation are major contributors to PD pathogenesis.Herein,ultrasmall nanoscale coordination polymers(NCPs)coordinated by ferric ions and natural product curcumin(Cur)were exploited,showing efficient neuroprotection by scavenging excessive radicals and suppressing neuroinflammation.In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse PD model,such ultrasmall Fe-Cur NCPs with prolonged blood circulation and BBB traversing capability could effectively alleviate oxidative stress,mitochondrial dysfunction,and inflammatory condition in the midbrain and striatum to reduce PD symptoms.Thus,this study puts forth a unique type of therapeutics-based NCPs that could be used for safe and efficient treatment of PD with potential in clinical translation.

Oral Sexual Behavior Among HIV-Infected Men Who Have Sex with Men--China,February 2021

Summary What is already known about this topic?Unprotected oral sex carries a risk of the transmission of sexually transmitted infections(STIs),especially if the individual has poor oral health.What is added by this report?Most human immunodeficiency virus(HIV)infected men who have sex with men(MSM)had never used a condom when giving oral sex(89.30%,718/804)or receiving oral sex(90.32%,709/785).Among MSM with detectable viral loads who had ever received oral sex without a condom,40.00%reported ejaculation in their partner’s mouth.

Optical bound states in the continuum in periodic structures:mechanisms,effects,and applications

Optical bound states in the continuum(BICs)have recently stimulated a research boom,accompanied by demonstrations of abundant exotic phenomena and applications.With ultrahigh quality(Q)factors,optical BICs have powerful abilities to trap light in optical structures from the continuum of propagation waves in free space.Besides the high Q factors enabled by the confined properties,many hidden topological characteristics were discovered in optical BICs.Especially in periodic structures with well-defined wave vectors,optical BICs were discovered to carry topological charges in momentum space,underlying many unique physical properties.Both high Q factors and topological vortex configurations in momentum space enabled by BICs bring new degrees of freedom to modulate light.BICs have enabled many novel discoveries in light-matter interactions and spin-orbit interactions of light,and BIC applications in lasing and sensing have also been well explored with many advantages.In this paper,we review recent developments of optical BICs in periodic structures,including the physical mechanisms of BICs,explored effects enabled by BICs,and applications of BICs.In the outlook part,we provide a perspective on future developments for BICs.